Background strain and the differential susceptibility of podocyte-specific deletion of Myh9 on murine models of experimental glomerulosclerosis and HIV nephropathy

We previously reported that podocyte-specific deletion of Myh9 (conventional myosin heavy chain 2A) in C57BL/6 mice does not cause spontaneous kidney disease but instead results in a predisposition to glomerulosclerosis in response to a second model of glomerular injury. In contrast, other investiga...

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Published in:PloS one 2013-07, Vol.8 (7), p.e67839
Main Authors: Johnstone, Duncan B, Ikizler, Omer, Zhang, Jidong, Holzman, Lawrence B
Format: Article
Language:English
Subjects:
Adults
African Americans
Aging
Agriculture
AIDS-Associated Nephropathy - genetics
AIDS-Associated Nephropathy - pathology
Analysis
Animal models
Animals
Anthracyclines
Bioinformatics
Biology
Diabetes
Disease control
Disease Models, Animal
Electrolytes
Female
Gene Deletion
Genetic Predisposition to Disease - genetics
Genotype & phenotype
Glomerulosclerosis, Focal Segmental - genetics
Glomerulosclerosis, Focal Segmental - pathology
Hematology
Histopathology
HIV
HIV-1 - physiology
House mouse
Human immunodeficiency virus
Hypersensitivity
Hypertension
Injuries
Kidney diseases
Male
Medicine
Mice
Mice, Congenic
Mice, Inbred C57BL
Mice, Inbred Strains - genetics
Mice, Transgenic
Muscle proteins
Mutation
Myosin
Myosin Heavy Chains
Nephropathy
Nonmuscle Myosin Type IIA - genetics
Organ Specificity - genetics
Podocytes - metabolism
Puromycin
Rodents
Sheep
Urine
Veterinary Science
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Ikizler, Omer
Zhang, Jidong
Holzman, Lawrence B
description We previously reported that podocyte-specific deletion of Myh9 (conventional myosin heavy chain 2A) in C57BL/6 mice does not cause spontaneous kidney disease but instead results in a predisposition to glomerulosclerosis in response to a second model of glomerular injury. In contrast, other investigators reported that podocyte-specific deletion of Myh9 (PodΔMyh9) resulted in spontaneous glomerulosclerosis in mice on a mixed background, suggesting that the glomerulosclerosis is dependent on background strain. In order to elucidate the cause of this strain dependent effect Podocin::Cre and Myh9(flox) alleles were backcrossed to mouse strain FVB/N, which is highly susceptible to glomerulosclerosis, with the aim of intercrossing susceptible FVB/N and resistant C57BL/6 mice in subsequent congenic analyses. However, after backcrossing mice to FVB/N and aging mice to 28 weeks, we found no evidence of glomerular disease in PodΔMyh9 mice vs control littermates (urine MAC ratio all p>0.05). We also tested C57BL/6 PodΔMyh9 mice for a predisposition to injury from models other than Adriamycin including HIV nephropathy (HIVAN), puromycin nephropathy, and sheep nephrotoxic serum. In the Tg26 model of HIVAN, we found that podocyte-specific deletion of Myh9 resulted in a modest hypersensitivity in adults compared to Tg26+ control littermates (urine MAC ratio, p
doi_str_mv 10.1371/journal.pone.0067839
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In contrast, other investigators reported that podocyte-specific deletion of Myh9 (PodΔMyh9) resulted in spontaneous glomerulosclerosis in mice on a mixed background, suggesting that the glomerulosclerosis is dependent on background strain. In order to elucidate the cause of this strain dependent effect Podocin::Cre and Myh9(flox) alleles were backcrossed to mouse strain FVB/N, which is highly susceptible to glomerulosclerosis, with the aim of intercrossing susceptible FVB/N and resistant C57BL/6 mice in subsequent congenic analyses. However, after backcrossing mice to FVB/N and aging mice to 28 weeks, we found no evidence of glomerular disease in PodΔMyh9 mice vs control littermates (urine MAC ratio all p&gt;0.05). We also tested C57BL/6 PodΔMyh9 mice for a predisposition to injury from models other than Adriamycin including HIV nephropathy (HIVAN), puromycin nephropathy, and sheep nephrotoxic serum. In the Tg26 model of HIVAN, we found that podocyte-specific deletion of Myh9 resulted in a modest hypersensitivity in adults compared to Tg26+ control littermates (urine MAC ratio, p&lt;0.05 or less). In contrast, we found that PodΔMyh9 mice were not predisposed to injury in response to other injury models including puromycin nephropathy and sheep nephrotoxic serum. While the mechanism of injury in these models is not fully understood, we conclude that PodΔMyh9 results in a variable susceptibility to glomerulosclerosis in response to different models of glomerular injury. 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In contrast, other investigators reported that podocyte-specific deletion of Myh9 (PodΔMyh9) resulted in spontaneous glomerulosclerosis in mice on a mixed background, suggesting that the glomerulosclerosis is dependent on background strain. In order to elucidate the cause of this strain dependent effect Podocin::Cre and Myh9(flox) alleles were backcrossed to mouse strain FVB/N, which is highly susceptible to glomerulosclerosis, with the aim of intercrossing susceptible FVB/N and resistant C57BL/6 mice in subsequent congenic analyses. However, after backcrossing mice to FVB/N and aging mice to 28 weeks, we found no evidence of glomerular disease in PodΔMyh9 mice vs control littermates (urine MAC ratio all p&gt;0.05). We also tested C57BL/6 PodΔMyh9 mice for a predisposition to injury from models other than Adriamycin including HIV nephropathy (HIVAN), puromycin nephropathy, and sheep nephrotoxic serum. In the Tg26 model of HIVAN, we found that podocyte-specific deletion of Myh9 resulted in a modest hypersensitivity in adults compared to Tg26+ control littermates (urine MAC ratio, p&lt;0.05 or less). In contrast, we found that PodΔMyh9 mice were not predisposed to injury in response to other injury models including puromycin nephropathy and sheep nephrotoxic serum. While the mechanism of injury in these models is not fully understood, we conclude that PodΔMyh9 results in a variable susceptibility to glomerulosclerosis in response to different models of glomerular injury. In addition, based on the lack of a spontaneous phenotype of glomerulosclerosis in both C57BL/6 and FVB/N mice, we propose that Myh9 is not absolutely required in adult podocytes.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23874454</pmid><doi>10.1371/journal.pone.0067839</doi><tpages>e67839</tpages><oa>free_for_read</oa></addata></record>
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subjects Adults
African Americans
Aging
Agriculture
AIDS-Associated Nephropathy - genetics
AIDS-Associated Nephropathy - pathology
Analysis
Animal models
Animals
Anthracyclines
Bioinformatics
Biology
Diabetes
Disease control
Disease Models, Animal
Electrolytes
Female
Gene Deletion
Genetic Predisposition to Disease - genetics
Genotype & phenotype
Glomerulosclerosis, Focal Segmental - genetics
Glomerulosclerosis, Focal Segmental - pathology
Hematology
Histopathology
HIV
HIV-1 - physiology
House mouse
Human immunodeficiency virus
Hypersensitivity
Hypertension
Injuries
Kidney diseases
Male
Medicine
Mice
Mice, Congenic
Mice, Inbred C57BL
Mice, Inbred Strains - genetics
Mice, Transgenic
Muscle proteins
Mutation
Myosin
Myosin Heavy Chains
Nephropathy
Nonmuscle Myosin Type IIA - genetics
Organ Specificity - genetics
Podocytes - metabolism
Puromycin
Rodents
Sheep
Urine
Veterinary Science
title Background strain and the differential susceptibility of podocyte-specific deletion of Myh9 on murine models of experimental glomerulosclerosis and HIV nephropathy
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